Drugs administered orally show medicinal effects through absorption, distribution, metabolism or elimination, and the intrinsic properties of a solid state, a salt state, a specific state of drug candidates are also significant in the drug development.
Different from thermodynamically stable crystalline state, amorphous solid has a thermodynamically very unstable state. Thus, the amorphous solid has a rapid elution rate and high solubility when compared to the crystalline solid. Accordingly, even though they are the same chemical compound, different bioavailability may be obtained.
Particularly, since the arriving rate of orally administered active ingredients to the blood of a patient is influenced by the elution rate, and the elution rate of the active ingredients from the gastrointestinal fluid of the patient plays an important role in attaining treating effects, the elution rate in an aqueous solution is significant. Among the drug states, the amorphous state dissolves fast and works fast with short duration time, however the crystalline state dissolves slowly and works slowly with long duration time.
Each of the solid state (crystalline or amorphous) drug candidates has different physical and chemical properties such as solubility, stability or reproduction capability. These properties may influence the final drug administration type, the optimized producing process, and the absorption in a human body, and the discovery of the most appropriate type for the drug development from now on may decrease time and costs necessary for the development.
Substantially, the acquisition of pure crystalline state and amorphous state, or even other noncrystalline state is very favorable in the drug development. These types may impart the chemical and physical properties of drug candidates with even better properties. Thus, the formation or the identification of the states for the combination of desired treating effects may become possible, and the preparation of a drug may become relatively easy. The solid phase crystalline state has more favorable pharmacological properties, is produced easily, and has better storing stability.
For the crystalline compounds having any states such as a dissolved state, the amount of residual solvents in a final drug may be small. In addition, through the crystallization, additional purification effect may be obtained. In addition, since this state is very stable during manufacturing a drug, the handling thereof during manufacturing is favorable.
The inventors of the present application has filed a patent application with the title of “10-ethoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthydine-5(6H)-on dichloride and a production method thereof”, represented by the following Chemical Formula, which has been registered with the Korean Patent Registration No. 10-0968175.

The 10-ethoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthydine-5(6H)-on dichloride is a tricyclic derivative having a poly(ADP-ribose) polymerase (PARP) inhibition activity, which may be advantageously used as an effective ingredient in a pharmaceutical composition for preventing or treating neuropathic pain, epilepsy, stroke, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, schizophrenia, chronic and acute pain, ischemic brain injury, neuronal loss after hypoxia, trauma and nerve damage, which are medical conditions induced by PARP overactivity.
However, for the preparation of the compound, an excessive amount of solvents is used in the case of mass production using column chromatography. Thus, mass production is difficult due to environmental problem, and much costs and time.
In addition, since 10-ethoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthydine-5(6H)-on dichloride anhydride absorbs humidity in the air, and the weight thereof may increase, careful handling is required. An amorphous 10-ethoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthydine-5(6H)-on dichloride absorbs humidity in the air fast and changes into a crystalline state unstably.
Therefore, the inventors of the present application have studied on a stable crystalline state of the 10-ethoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthydine-5(6H)-on dichloride to solve the above-described defects, obtained a stable crystalline state of a 10-ethoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthydine-5(6H)-on compound in a high yield, and suggested a separation method to complete the present invention.